JP2003534309A - Preparation of enantiomer-rich amine-functionalized compounds - Google Patents

Abstract

  (57) [Summary] In the preparation of an enantiomerically enriched amine-functionalized compound, in a method of removing a residue fragment of a chiral modification from a diastereomer compound of formula (2), the diastereomer compound comprises a residue of the chiral modification. A process wherein the carbon atom to be subjected to non-reductive removal has an oxidation state of +3, which cannot be reduced during the removal process. The chiral modification is preferably an amide or ester of a protein-derived amino acid, or phenylglycinamide, an ester of phenylglycine, an ester of p-OH-phenylglycinamide, an ester of p-OH-phenylglycine, α-methylphenylglycine. It is selected from the group of amides and esters of α-methylphenylglycine.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD OF THE INVENTION

The present invention provides for the preparation of enantiomerically enriched amine-functionalized compounds of formula 1
It relates to a method of removing a residue fragment of a chiral modification. Formula (1) In the formula, R ₂ , R ₃ , and R ₄ are different from each other, and are H, a substituted or unsubstituted (cyclic) alkyl group, an alkenyl group, an aryl group, or a ring having one or more N, O, or S atoms. or acyclic heteroalkyl group or heteroaryl group, or (CH _{2) n} -
COR ₆ , where n = 1, 2, 3, ... 6 and R ₆ = OH, eg C of 1-20
It represents a substituted or unsubstituted alkyl group, aryl group or alkoxy group having an atom or a substituted or unsubstituted amino group. According to the method of the present invention, the diastereomeric compound of formula (2) (Wherein R ₂ , R ₃ and R ₄ are as defined above, R ₁ and R ₅ are different from each other, R ₁ is a modified or unmodified side chain of an amino acid derived from a protein, or Represents a substituted or unsubstituted phenyl group, R ₅ is H or a lower alkyl group, for example, C ₁ -C ₅
Represents an alkyl group of the formula, where X = O and Y = OR, where R is H or C ₁
Represents an alkyl group -C _7, or Y = NR ₇ R _8, wherein R ₇ and R ₈ are each, independently, H, for example, having 1 to 20 C atoms (cyclic) alkyl group, an alkenyl group, Or an aryl group, or X and Y together represent N) undergoing non-reductive removal of the residue fragment of the chiral modification, the carbon atom being removed having an oxidation state of +3, It cannot be lowered during the removal process.

[0002]

[Prior art]

In the literature, examples of production methods are known in which enantiomerically enriched chiral modifications, such as enantiomerically enriched valine esters, have been applied to the preparation of enantiomerically enriched compounds; see, for example, Basile, T. et al. J .; Org. Chem. , 59 (25)
, 7766-7773 (1994). As starting materials, suitable prochiral compounds corresponding to the desired enantiomerically enriched compound and enantiomerically enriched esters of valine are utilized as chiral modifiers. In a known manner, diastereomeric compounds are formed which, after removal of the residual fragment of the chiral modification, give the desired enantiomerically enriched compound.

[0003]

[Problems to be Solved by the Invention]

In these known methods, residue fragment removal of chiral modifications, as described in the references cited above, usually involves reduction of the ester with a hydride, for example to the corresponding amino alcohol with LiAlH ₄ or NaBH ₄ . Reduction of,
It occurs via subsequent oxidative cleavage using, for example, H ₅ IO ₆ / CH ₃ NH ₂ . However, the hydride complexes used are rather expensive and require special safety measures when used on a large scale. Moreover, the cost of oxidative cleavage is quite high.

[0004]

[Means for Solving the Problems]

The present invention now provides a route to enantiomerically enriched compounds without the disadvantages mentioned above.

Applicants have now found a very attractive route based on the use of amino acids or their derivatives as chiral modifiers, where they are simple without the use of known reducing and / or oxidizing agents. Residue fragments can be removed in various ways,
. Preferably, an inexpensive amino acid, particularly an amino acid derived from a protein, such as aspartic acid, glutamic acid, methionine, or valine, or an inexpensive non-protein derived amino acid, such as phenylglycine, p-hydroxyphenylglycine, or α-methylphenylglycine. The derivatives, especially amides or esters, are used as the chiral modification moiety.

[0006]

DETAILED DESCRIPTION OF THE INVENTION

The preparation of enantiomerically enriched compounds of formula 2 can be carried out according to known chemical conversions. The compound of formula 2 is an enantiomerically enriched amino acid derivative of formula 4 (In the formula, R ₁ and R ₅ have the meanings described above, Z is OH, a C ₁ -C ₇ alkoxy group, or NR ₇ R ₈ , where R ₇ and R ₈ are each independently H. Represents a (cyclic) alkyl group, alkenyl group, or aryl group, having, for example, 1 to 20 C atoms)
Is a compound of formula 5 (Wherein R ₂ and R ₃ have the meanings given above) using the corresponding Schiff base (
Can be prepared by converting the resulting Schiff base to an enantiomerically enriched compound having formula 2 with a reducing agent or an organometallic compound (see Figure 1). . When an amino acid is used as a chiral modification,
Schiff bases are usually prepared and used as carboxylates.

In the production method of the present invention, the residue fragment is removed from the chiral modification part without reducing the carbon atom of the amino acid fragment to be removed-represented by Formula 2. In the process of removing the residue fragment, the compound of formula 3 may be produced. Formula 3 In the formula, R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are as described above. This compound of formula 3 can subsequently be converted in a known manner to the corresponding amine-functionalized compound of formula 1. See Figure 2, for example.

When an amino acid amide whose amide group is unsubstituted (R ₇ and R ₈ are H) is used as the chiral modifier, the residue fragment of the chiral modifier is described, for example, in J. Am. March, Advanced Organic Chemistry,
Fourth Edition, Wiley-Interscience, New York, 1992.
, 1041-1042, in a known manner, for example by dehydration of the amide group to a nitrile. For dehydration, the amide is converted into SOCl ₂ , P
It may be performed by treatment with OCl ₃ , PCl ₅ , p-TosCl / pyridine, Tf ₂ O / pyridine, or Vilsmeier reagent in combination with an organic or inorganic base. Vilsmeier reagent can be prepared by reacting dimethylformamide (DMF) with oxalyl chloride in acetonitrile, methylene chloride, chloroform, dioxane, tetrahydrofuran (THF), or diethyl ether. In a general method, the Vilsmeier reagent is produced in the desired solvent, for example at a temperature between 0 ° C. and room temperature. Generation is usually 5
It will be completed in ~ 15 minutes. In a preferred embodiment, a solution of the amide in the desired solvent is added dropwise to the Vilsmeier reagent at a temperature between 0 ° C and room temperature. The addition will usually be completed in 10-20 minutes. 2 for the production of nitril
An equivalent amount of base is added. Preferably organic bases such as pyridine or triethylamine (TEA) are used. Inorganic bases may also be effective. The deprotection procedure most often proceeds with conformational retention at the newly formed stereocenter. More particularly, the Applicant has found that dehydration of the amide with oxalyl chloride / DMF at room temperature with pyridine as the base occurs almost quantitatively. The resulting amino nitrile is subsequently passed on to Retro-Strecker (St
recker) reaction, for example treatment at elevated temperature, for example at a temperature between room temperature and the reflux temperature of the selected solvent, can be converted to the corresponding imine. Suitable solvents which can be used are any inert solvents, in which a reasonable amount of all reaction components are soluble. Treatment of the nitrile with an organic or inorganic base in a protic solvent also results in elimination of HCN. In a preferred embodiment, the nitrile is added 1.5-3 equivalents, such as KOH or ethanol suspension of K ₂ CO _3. Refluxing the mixture for about 1 to 3 hours results in complete elimination of HCN. Examples of suitable bases are alkali (earth) metal hydroxides, alkali (earth) metal carbonates, and organic bases such as tertiary amines. Alternatively, brief heating of the crude imine at elevated temperature (> 100 ° C.) and reduced pressure is also possible. Optimal temperatures and pressures depend on the reaction system involved and can be readily determined by one of ordinary skill in the art. As an example, conversion of a nitrile to an imine at a temperature of 160 ° C. will usually take several minutes.

The imine is subsequently added to the corresponding amine-functionalized compound in a known manner, for example with a strong aqueous acid at an elevated temperature, eg between room temperature and reflux temperature, eg 30% H 2.
It can be converted by treatment with Cl. Another common method is, for example, the transfer of a fragment containing the imine carbon to a hydrazine or oxime.
It has been found that treatment with, for example, hydroxylamine in a water / tetrahydrofuran (THF) mixture, or phenylhydrazine in hexane, is a particularly mild method and produces amine-functionalized compounds almost quantitatively.

When an amino acid amide is utilized as the chiral modifier, the amide group is first hydrolyzed according to known methods for amide hydrolysis, for example acid, alkali, enzymatic or oxidative hydrolysis, to yield the corresponding carboxyl group. And treating with, for example, a strong aqueous acid, such as 15% to 30% HCl, at elevated temperature, such as between room temperature and reflux temperature, followed by a reaction resulting in total removal of CO ₂ groups. Also seems possible. In one embodiment, a solution of the amide in aqueous HCl is refluxed overnight. Neutralization of the cooled solution with a base such as aqueous NaOH results in precipitation of the amino acid. Alternatively, see, for example, Vaughn, Robbins, J .;
Org. Chem. , 1975, 40, 1187, the amide is treated with Na ₂ O ₂ in water. Refluxing the reaction mixture overnight gives the amino acid quantitatively. The latter method gives better results due to less decomposition. Removal of CO ₂ occurs via decarbonylation or decarboxylation, for example by conversion of a carboxyl group into a group that is easily removed, such as mesylate, tosylate, or acid chloride, followed by treatment with a base to decarboxylate or imine. To generate. Specific examples are described in J. C. Sheehan, J .; W. Frankenfeld, J .; Org.
Chem. , 1962, 27, 628-629, with pyridine / p-toluenesulfonyl chloride. An especially mild removal embodiment was found to be treatment with oxalyl chloride / dimethylformamide (DMF) (Vilsmeier reagent) using triethylamine as base, or treatment with trifluoromethanesulfonic anhydride and triethylamine. An alternative method is, for example, treatment of SOCl ₂ , PCl ₅ , COCl ₂ with p-TosCl, and triethylamine. This reaction is performed, for example, in an aprotic solvent such as acetonitrile, methylene chloride, chloroform, dioxane, THF.
Or in diethyl ether. Of course, it is also possible to choose a non-nucleophilic base other than triethylamine. The imine can then be converted to the corresponding amine-functionalized compound, as described above.

When an amino acid ester is used as the chiral modifier, the residue fragment produces the corresponding amino acid amide, for example by conversion with ammonia, which in one of the methods described above then Can be removed by conversion to an amine-functionalized compound that

When an amino acid ester is used as the chiral modifier, as described above, the chiral amine-functionalized compound can be treated, for example, by treatment with an acid to hydrolyze the ester to an acid, followed by residue fragmentation. It can also be obtained by removal and conversion of the imine to the corresponding chiral amine. The ester is, for example,
The ester may be converted to the amino acid by stirring the ester in a solution of NaOH in methanol under standard hydrolysis conditions, eg at room temperature for 3 days. The deprotection procedure most often proceeds with conformational retention at the newly formed stereocenter.

When an amino acid amide in which the amide group is not substituted (R ₇ ═R ₈ ═H) is used as the chiral modifier, the residue fragment of the chiral modifier is as described above.
It can be converted to an amino nitrile by dehydration, followed by alcohol and acid (
It can be converted to an amino acid ester, for example by treatment with (methanol / HCl), which can subsequently be converted to the corresponding chiral amine-functionalized compound, as described above.

[0014]

【Example】

The invention will now be described on the basis of examples, without being restricted thereby. Example 1 Synthesis of an imine of (R) -phenylglycine amide and isobutyraldehyde 7.5 g (50 mmol) (R) of 3.6 g (50 mmol) of isobutyraldehyde and 0.7 g of 4Å sieve in 50 ml of methylene chloride. -Added to phenylglycinamide. The mixture was stirred for 4 hours at 20-25 ° C.
After filtration, the solution was concentrated. 10.6 g (45.0 mmol, 95%) of (R) phenylglycinamide and Schiff base of isobutyraldehyde were obtained as a white solid.

Example II Allylation of (R) -phenylglycine amide and isobutyraldehyde imine 4.1 g (20.0 mmol) of (R) -phenylglycine amide and isobutyraldehyde Schiff base in 100 ml of dry THF and Activated Zn (2
An exothermic reaction occurred when 2.4 g (20 mmol) of allyl bromide was added to the (eq.) Mixture with stirring. The mixture was stirred for 1 h at 20-25 ° C., followed by the addition of 100 ml saturated aqueous NaHCO ₃ . 100 ml of ethyl acetate was added to this. After separation of the ethyl acetate layer, the aqueous layer was extracted again with 100 ml of ethyl acetate. After drying over MgSO ₄ , filtration and evaporation, 3.8 g (
(15.4 mmol, 77%) of homoallylamine was obtained as a yellow oil. ¹ H NMR gave only one stereoisomer.

Example III Dehydration of the homoallylamine of Example II to produce the nitrile, followed by conversion to imine Acetonitrile (100 ml) was cooled to 0 ° C. and then DMF (0.88 g).
, 12.0 mmol, 0.93 mL) and oxalyl chloride (1.54 g, 12.
0 mmol, 1.06 mL) was added. After stirring for 15 minutes at 0 ° C., a solution of the homoallylamine adduct of Example II (2.0 grams, 8.1 mmol) in acetonitrile (100 ml) was subsequently added. After stirring for 15 minutes, pyridine was added (1.88 g, 24.0 mmol, 1.93 mL) and after heating for another 15 minutes at room temperature water was added (200 ml) and the mixture was Extracted with methylene chloride (2 x 50 ml). Evaporation of the solvent gave an orange oil consisting of a mixture of nitrile and imine. The mixture was subsequently heated with a heat gun for 5 minutes (300 ° C.) giving an imine yield of 44% (0.8 g, 3.5 mmol). Example IIIa Dehydration of amide to nitrile with oxalyl chloride / DMF and TEA To methylene chloride (600 mL) cooled in an ice bath, DMF (144.0 mmo).
1, 10.56 g, 11.16 mL) was added. Oxalyl chloride (144.
0 mmol, 18.48 g, 12.72 mL) was added dropwise. Gas (CO and C
After the O ₂ ) evolution was over, the amide of Example II (97.6 mmol, 24.0 g)
) In methylene chloride (100 mL) was added dropwise over 10 minutes. Triethylamine (95.5 mmol, 9.87 g, 13.48 mL) was added dropwise over 5 minutes and the reaction was stirred at room temperature for 30 minutes. Water (500 mL) was added and the organic phase was separated. The organic layer was dried over Na ₂ SO ₄ and filtered. Evaporation of solvent gave a red oil (22.0 grams). The red oil was dissolved in a mixed solvent of ethyl acetate / heptane (1/5) and filtered through a short silica filter. Evaporation of the solvent under reduced pressure at 30 ° C. gave a yellow oil consisting of the pure product nitrile (17).
． 4 grams, 78%).

Example IV Hydrolysis of the Amide of Example II to Carboxylic Acid The homoallylamide of Example II (3.0 g, 11.5 mmol) was added to 15% aqueous HCl (75 mL). The mixture was boiled for 3 hours. The water was vaporized. The product was isolated as the HCl salt (light brown solid): 3.17 grams (10.
7 mmol; 93%).

Example V Conversion of Carboxylic Acid of Example IV to Imine DMF (15 mmol, 1 mmol) in acetonitrile (100 mL) cooled in an ice bath.
． 10 g, 1.16 mL) was added. Oxalyl chloride (15 mmol, 1.
90 g, 1.30 mL) was added dropwise. After the evolution of gases (CO and CO ₂ ) had ended, the carboxylic acid of Example IV (10 mmol, 2.49 g) was added in one portion. The mixture was stirred for 15 minutes producing a clear yellow solution. TEA (30mm
ol, 3.0 g, 4.2 mL) was added dropwise keeping the temperature below 10 ° C.
Gas evolved (CO), the reaction mixture became orange / yellow and a precipitate formed. The reaction mixture was stirred for 15 minutes. The ice bath was removed and H ₂ O (200 mL) was added. The mixture was extracted with _{Et 2 O (2 × 50mL)} . Et ₂ O was evaporated and the residue was dissolved in CHCl ₃ (50 mL). The organic phase was washed once with H ₂ O (50 mL). CHCl ₃ was dried over MgSO ₄ and filtered. Evaporation of filtrate (R)
This gives an imine (yellow oil, 89%).

EXAMPLE VI Conversion of the imine of Examples III and V to an amine: Using phenylhydrazine, the imine, 3.3 g (16.6 mmol), was dissolved in hexane (50 ml). 1.66 ml of phenylhydrazine (16.6 mmol) was added and the reaction mixture was stirred at room temperature for 18 hours. After filtration through a glass filter, water was added followed by acidification with HCl (30%). The hexane layer was separated and the aqueous phase was made basic with NaOH (33%). The product was extracted with hexane (2 x 50 mL). The hexane solution was dried over MgSO ₄ , filtered and evaporated. After evaporation, the product was isolated as an orange oil. 1.7 g (15.
3 mmol, 92%).

Example VII Conversion of the imine of Examples III and V to amine: The imine (2.0 g, 9.9 mmol) was dissolved in 50% aqueous THF (50 ml) using hydroxyamine. Hydroxylamine HCl salt (2.1 g, 29.8 mmol) was added and the reaction mixture was stirred at room temperature for 18 hours. THF was evaporated in vacuo and the residue was acidified with HCl (30%) to pH = 1. The aqueous phase was subsequently extracted with ethyl acetate (2 x 50 ml). The aqueous phase was then basified with NaOH (33%) and the product was extracted with hexane (2 x 50 ml). The hexane solution was dried over MgSO ₄ , filtered and evaporated. After evaporation, the product was isolated as a yellow oil: 0.68 g (5.9 mmol, 60%). NMR data is the same as in Example VI.

Example VIII The crude mixture obtained in Example III was subjected to 160 minutes under reduced pressure until the nitrile was quantitatively converted to (R) imine (orange oil, 44% based on amide) for 160 minutes. Heated at ° C.

Example IX The nitrile of Example IIIa (32.5 mmol; 7.4 g) was treated with ethanol (15
0 mL). K ₂ CO ₃ (2 eq; 64.9 mmol; 8.97 g) was added. The reaction mixture was refluxed for 2 hours. After cooling the reaction mixture to room temperature, the solvent was evaporated. The residue was mixed with water (100 mL) and methylene chloride (100 mL). The organic phase was separated, dried over Na ₂ SO ₄ and filtered. The solvent was evaporated to give the imine as a yellow oil (6.2g; 84%).

Example X The amide of Example II (25.2 mmol, 6.3 g) was mixed with water (40 mL). At room temperature, solid Na ₂ O ₂ (27.7 mmol, 2.2 g, 1.1 eq) was added and the mixture was refluxed for 18 hours. The reaction mixture was cooled to room temperature and neutralized to pH = 6-7 with aqueous HCl (30%). The precipitate is filtered off,
Dried (colorless powder, 84%, mixture of two diastereomers 60:40)
. Due to racemization of the chiral modification (phenylglycine), two diastereomers were generated. The amine obtained after removal of the modification was found to be enantiomerically pure. m. p. 75-76 ° C.

Example XI Dehydration of amides to nitriles with triflic anhydride Anhydrous bath-cooled methylene chloride (250 mL) was added to the amides of Example II (69.1).
mmol, 14.0 g) and triethylamine (114.1 mmol; 11.8).
g; 16.1 mL) was added. Triflic anhydride (68.4 mmol,
(19.3 g, 11.5 mL) was added dropwise over 5 minutes and the reaction was warmed to room temperature.
The reaction mixture was stirred at room temperature for 30 minutes. H ₂ O (250 mL) was added and the organic phase was separated. The organic layer was dried over Na ₂ SO ₄ and filtered. Evaporation of the solvent resulted in an orange oil (11%) consisting of a mixture of nitrile (80%) and imine (20%).
． 9g) was given.

Example XII To a solution of the amide of Example II (18.8 mmol; 4.63 g) in methylene chloride (100 mL) cooled in an ice bath, triethylamine (37.6 mmol; 5).
． 28 mL) and oxalyl chloride (18.8 mmol; 1.64 mL) were added. The color changed to orange and gas evolved. The reaction mixture was warmed to room temperature and water (100 mL) was added. The organic phase was separated. The organic layer was dried over Na ₂ SO ₄ and filtered. Evaporation of solvent gave a red oil (5.0 grams). The red oil was dissolved in a mixture of EtAc / heptane (1/5) and filtered through a short silica filter. Evaporation of the solvent under reduced pressure at 30 ° C. gave a yellow oil of the nitrile (1.5 grams, 32%).

Example XIII Cooled (ice bath), N-benzylidene-DL-valine amide (29.5 mmo)
1; 5 g, prepared from DL-valine amide and benzaldehyde) THF
To a solution in (25 mL), TH of allyl zinc bromide (1.5 eq) prepared from zinc wool (2.85 g) and allyl bromide (3.8 mL).
The F (25 mL) solution was added. The reaction mixture was warmed to room temperature, 100 mL
Poured into the water. The product was extracted with ethyl acetate (200 mL). Organic phase is N
It was dried over a ₂ SO ₄ and filtered. The solvent was evaporated and the racemic N- (1-phenyl-3-buten-1-yl) valinamide was converted to diastereomeric ratio> 95: 5.
Remained as an oil at. Upon addition of heptane, the oil solidified. Yield: 4
． 5g, 76%

Example XIV DMF (5.4 mmol, 0.3) in methylene chloride (50 mL) cooled in an ice bath.
9 g, 0.42 mL) was added. Oxalyl chloride (5.4 mmol, 0.6
9 g, 0.48 mL) was added dropwise. After generation of gas (CO and CO ₂₎ has been completed, in Example XIII N-(1-phenyl-3-buten-1-yl) - valinamide (3.6 mmol, 0.89 g) are all added in one portion It was Triethylamine (3.6 mmol, 0.51 mL) was added dropwise over 5 minutes and the reaction was stirred at room temperature for 30 minutes. H ₂ O (50 mL) was added and the organic phase was separated.
The organic layer was dried over Na ₂ SO ₄ and filtered. Evaporation of the solvent gave the corresponding aminonitrile product as a yellow oil (0.78g; 95%).

Example XV The aminonitrile of Example XIV (3.4 mmol; 0.78 g) was added to ethanol (
50 mL). K ₂ CO ₃ (2 eq; 6.8 mmol; 0.93 g) was added. The reaction mixture was refluxed overnight. After cooling the reaction mixture to room temperature, the solvent was evaporated. The residue was mixed with water (50 mL) and DCM (50 mL). The organic phase was separated, dried over Na ₂ SO ₄ and filtered. The solvent is vaporized and 0.6 g
To give a yellow oil. According to ¹ H-NMR spectroscopy, the crude product is N-i-
It contained a mixture of butylidene-1-amino-1-phenylbutene-3 (82%) and starting aminonitrile (18%). ¹ H NMR of imine (200M
Hz, CDCl ₃ )

Example XVI The imine obtained in Example XV (0.5 g, 2.5 mmol) was treated with 50% aqueous THF.
It was dissolved in (50 mL). To this solution was added 3 equivalents of NH ₂ OH.HCl (0.52
g, 7.45 mmol) was added and the reaction mixture was stirred at ambient temperature overnight. THF was evaporated under reduced pressure and the residue was treated with aqueous HCl (30%) until pH = 1. The aqueous phase was extracted with EtOAc. Aqueous phase is p with aqueous NaOH (33%)
Adjusted to H = 10 and extracted with CH ₂ Cl ₂ . After drying over Na ₂ SO ₄ , the solvent was evaporated to give 1-amino-1-phenylbutene-3 (colorless oil, 76%
). ¹ H NMR (200 MHz, CDCl ₃ )

─────────────────────────────────────────────────── ─── Continued front page    (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, I T, LU, MC, NL, PT, SE, TR), OA (BF , BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, G M, KE, LS, MW, MZ, SD, SL, SZ, TZ , UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, B Z, CA, CH, CN, CO, CR, CU, CZ, DE , DK, DM, DZ, EC, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, I N, IS, JP, KE, KG, KP, KR, KZ, LC , LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, MZ, NO, NZ, P L, PT, RO, RU, SD, SE, SG, SI, SK , SL, TJ, TM, TR, TT, TZ, UA, UG, US, UZ, VN, YU, ZA, ZW (72) Inventor Broxtelman, Kirinus, Bernarda             Su             Netherlands, 6151 JA Sitta             De Gerestrad 11 (72) Inventor Delange, Ben             Netherlands, 6151 Jimunster             Guerlain, Burg. Louis Tenstraat               29 F-term (reference) 4H006 AA02 AC52 AC54 AC59 AC81

Claims (12)

[Claims] 1. A method for removing a residue fragment of a chiral modification in the preparation of an enantiomerically enriched amine-functionalized compound of formula 1, wherein the diastereomeric compound of formula 2 comprises a chiral modification of The method wherein the carbon atom undergoing non-reductive removal of the residue fragment is removed and has a +3 oxidation state, which oxidation state is not lowered during the removal method. Formula (1) (In the formula, R ₂ , R ₃ and R ₄ are different from each other, and are H, a substituted or unsubstituted (cyclic) alkyl group, an alkenyl group, an aryl group, a cyclic group having one or more N, O, or S atoms, or acyclic heteroalkyl group or heteroaryl group, or (CH _{2) n} -CO
R ₆ , where n = 1, 2, 3, ... 6 and R ₆ = OH, represents a substituted or unsubstituted alkyl group, aryl group, alkoxy group, or amino group) Formula (2) (Wherein R ₂ , R ₃ , R ₄ are as defined above, R ₁ and R ₅ are different from each other, R ₁ is a modified or unmodified side chain of a protein-derived amino acid, or Represents a substituted or unsubstituted phenyl group, R ₅ represents H or a lower alkyl group, X═O and Y═OR, wherein R is H or a C ₁ -C ₇ alkyl group, or NR ₇ R ₈ ; Here, R ₇ and R ₈ each independently represent H, a (cyclic) alkyl group, an alkenyl group, or an aryl group, or X and Y together represent N. 2. A compound having formula (3) is formed by non-reductive removal of residue fragments, (Where R ₁ , R ₂ , R ₃ , R ₄ , and R ₅ are as described above), then the compound having formula (3) is (in a known manner) treated with the corresponding amine functionalization. The method of claim 1, wherein the method is converted to a compound. 3. The method according to claim 1 or 2, wherein the chiral modification is selected from the group of amides or esters of protein-derived amino acids. 4. The chiral modification moiety is phenylglycine amide, phenylglycine ester, p-OH-phenylglycine amide, p-OH-phenylglycine ester, α-methylphenylglycineamide and α-methylphenylglycine ester. The method according to any one of claims 1 to 3, selected from the group of: 5. The residue fragment is derived from an amino acid amide in which the amide group is not substituted, and the residue fragment is formed into an imine by dehydration of the amide group to a nitrile group, followed by a retro-Strecker reaction. And the method of any one of claims 1 to 4, wherein the imine is removed by conversion to the corresponding chiral amine-functionalized compound. 6. Dehydration of an amide group to a nitrile group transforms the amide into a Vilsmeier (V
The method of claim 5, which is carried out by treating with an ilsmeier reagent. 7. A reaction wherein the residue fragment is derived from an amino acid amide, wherein the residue fragment hydrolyzes the amide group to a carboxyl group, followed by the total removal of the CO ₂ group to form an imine. 5. A method according to any one of claims 1 to 4, wherein the imine is removed by conversion to the corresponding chiral amine functionalized compound. 8. A residue fragment is derived from an ester of an amino acid, wherein the residue fragment is converted to the corresponding amide of the ester with ammonia, after which the residue fragment is removed according to claims 5-6. The method according to claim 1, wherein the method is removed. 9. The residue fragment is derived from an ester, the residue fragment comprising:
Removal by means of hydrolysis of an ester group to a carboxyl group, followed by a reaction resulting in the total removal of a CO ₂ group to form an imine, and conversion of the imine to the corresponding chiral amine-functionalized compound. The method according to any one of 1 to 4. 10. The residue fragment is derived from an amino acid amide in which the amide group is not substituted, and the residue fragment is formed into an ester group by dehydration of the amide group to a nitrile group and subsequent treatment with alcohol and acid, Thereafter, the residue fragment is removed by being removed according to claim 7 or 8.
The method according to any one of 4 above. 11. A compound of formula 2 wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , X, and Y are as described above, and a compound of formula 4 (Here, R ₁ and R ₅ have the meanings described above, Z represents OH, C ₁ -C ₇ alkoxy group, or NR ₇ R ₈ , and R ₇ and R ₈ are each independently H, ( (Representing a cyclic) alkyl group, alkenyl group, or aryl group), and an enantiomerically enriched amino acid derivative having the formula (5) (Wherein R ₂ and R ₃ have the meanings given above) to the corresponding Schiff bases, and subsequently the resulting Schiff bases, with reducing agents or organometallic compounds, have the formula 2 11. A method according to any one of claims 1-10, which is first prepared by conversion to an enantiomerically enriched compound. 12. The process according to claim 1, wherein the resulting enantiomerically enriched amine-functionalized compound is subsequently used in the preparation of pesticides or pharmaceuticals.